<p>Managing Disease-Modifying Therapies and Breakthrough Activity in Multiple Sclerosis Patients During the COVID-19 Pandemic: Toward an Optimized Approach</p>

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R E V I E W

Managing Disease-Modifying Therapies and

Breakthrough Activity in Multiple Sclerosis

Patients During the COVID-19 Pandemic: Toward

an Optimized Approach

This article was published in the following Dove Press journal: Therapeutics and Clinical Risk Management

Sherif M Hamdy1

Maged Abdel-Naseer 1 Hatem S Shehata 1

Amr Hassan 1

Alaa Elmazny 1 Nevin M Shalaby1 Noha T Abokrysha1 Nirmeen A Kishk1

Mona AF Nada 1

Sandra M Ahmed1

Mohamed I Hegazy 1

Doaa Mekkawy1

Husam S Mourad 1

Ahmed Abdelalim 1 Thomas Berger 2

1_{Neurology Department, Faculty of} Medicine, Cairo University, Cairo, Egypt; 2_{Neurology Department, Medical} University of Vienna, Vienna, Austria

Abstract:The emergence of the novel coronavirus disease 2019 (COVID-19) pandemic has

become a major public health challenge of global concern since December 2019, when the virus was recognized in Wuhan, the capital city of Hubei province in China and epicenter of the COVID-19 epidemic. Given the novelty of COVID-19 and the lack of speciﬁc anti-virus therapies, the current management is essentially supportive. There is an absence of consensus on guidelines or treatment strategies for complex disorders such as multiple sclerosis (MS), in which the risk of infections is higher than in the general population. This is due to the overall impairment of the immune system typical of autoimmune diseases, in addition to accumulation of disabilities, and the iatrogenic effect generated by corticosteroids and the recommended disease-modifying therapies (DMTs). DMTs have different modes of action, but all modulate and interfere with the patient’s immune response, thereby raising concerns about adverse effects, such as an increased susceptibility to infections. In this review, we analyze the evidence for use of DMTs during the current critical period and ratify an algorithmic approach for management to optimize care between keeping DMTs, with their infection hazards, or coming off them, with the risk of disease activation. We also provide an algorithmic approach to the management of breakthrough activity during the COVID-19 pandemic.

Keywords:COVID-19, multiple sclerosis, disease-modifying therapies

Introduction

The novel coronavirus disease 2019 (COVID-19) pandemic is a world-shattering infection that affects all geographical areas. The current situation is changing rapidly, with increasing numbers of cases arising across more than 200 countries

and territories around the world.1The number of conﬁrmed coronavirus patients has

grown substantially, with higher day-to-day increases and evidence of sustained transmission in six continents.2

The novel coronavirus is a member of the beta group of coronaviruses, which was named by the International Committee on Taxonomy of Viruses (ICTV) as severe acute

respiratory syndrome–coronavirus-2 (SARS-CoV-2) and the disease as COVID-19.3

Accumulating evidence suggests that a subgroup of patients with severe COVID-19

may have alveolitis cytokine storm syndrome.4 Secondary hemophagocytic

lymphohistiocytosis (sHLH) is an underrecognized, hyperinﬂammatory syndrome

Correspondence: Amr Hassan Kasr Al Ainy Faculty of Medicine, Cairo University, P.O.11553, Cairo, Egypt Tel +201006060809

Email [email protected]

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characterized by a fulminant and fatal hypercytokinemia with multiorgan failure, which is most commonly triggered by viral infections5and characterized by an increase in pro-inﬂammatory mediators.6

There is a great complexity of host immune defenses against viral infections. Activation of cytotoxic and other T lymphocytes (cell-mediated immunity) occurs as early as 3–4 days,7then decreases rapidly within 5–10 days of elimination of the virus. In contrast, humoral immunity appears later (after 7 days) and persists for much longer (often for years).8

The knowledge that COVID-19 can cause critical ill-ness and death is a particular concern among patients with chronic illnesses, including multiple sclerosis (MS).9

COVID-19 Infection Risk

Strati

ﬁ

cation in Patients with

Multiple Sclerosis

A3B2 tlsb -0.02w?>Patients with multiple sclerosis (pwMS) seem to be at higher risk of infection compared with the general population,10and constitute a susceptible population for contracting COVID-19 and frequently devel-oping respiratory insufﬁciency as a result of their reduced muscle strength, bulbar dysfunction and ineffective

secre-tion clearance;11however, not all patients carry the same

risk. Nevertheless, COVID-19 risk can be increased by

comorbidities, older age and degree of disability.

Moreover, many disease-modifying therapies (DMTs) with various modes of action modulate or interfere with the patient’s immune response, raising uncertainties about

the increased risk of infection.12 According to their risk

category, patients should be advised about the appropriate mitigation measures, by practicing social distancing for patients with low risk, social stringency for patients with intermediate risk or shielding for patients with high risk (Table 1).

During the current COVID-19 pandemic, pwMS as well as MS specialists are faced with many challenges: (1) concerns about the use of DMTs in MS patients; (2)

delay or deferral in DMT dispensing due to logistic difﬁ

-culties; (3) shortage of available hospital beds; (4)

patients’ worries about using

immunosuppressive/immu-nomodulatory treatments; (5) absence of blanket recom-mendations or consensus regarding maintenance therapy and relapse management; and (6) the need for coordinated efforts to raise awareness among patients and medical

society about general and speciﬁc infection control

measures according to World Health Organization

(WHO) recommendations.

The present review discusses the general prophylactic measures for pwMS to mitigate the risk of infection, initiation/maintenance of DMTs and acute relapse manage-ment, and tries to design strategies for MS management during the current COVID-19 pandemic.

General Infection Risk Mitigation

Measures

PwMS should adopt the recommended general and national public health measures, including frequent handwashing/ sanitation, social distancing and adequate nutrition.13 For patients who have interactive audio/video telecommunica-tions facilities, telehealth services, e-visits and virtual check-ins are implemented. In the absence of such means, especially in rural settings, phone calls/WhatsApp texting with the MS team should be available for regular follow-up and for answering patients’queries. Public awareness should be raised through social media campaigns to provide essen-tial information and knowledge about COVID-19, and to

reinforce key messages to shape patients’ behavior to

pre-vent/minimize the spread of infection.

Initiation/Maintenance of DMTs

The initiation and maintenance of DMTs in pwMS can be very challenging, especially during this critical period. A few DMTs exert immunomodulatory effects with almost no increase in the risk of systemic infections. Other agents used in MS management have immunosuppressive effects with considerable effects on lymphocyte count, trafﬁcking, proliferation, differentiation and function, leading to an

increased risk of infections.14 Table 2 summarizes the

modes of action, doses and routes of administration of currently approved DMTs.

Interferon-Beta (INF-

β

)

The therapeutic efﬁcacy of INF-βin MS is not only related to its immunoregulatory characteristics, but also to its in vivo anti-viral properties, evident by their signiﬁcant inhibition on the viral replication of human herpesvirus 6 (HHV-6), which was studied as an example of a latent neurotropic virus.15

Leukopenia/neutropenia and, to a lesser extent,

lym-phopenia are among the very rare hematological

abnormalities associated with INF-β use; thus, they are

usually clinically insigniﬁcant.16 INF-βinitiation can be

Hamdy et al Dovepress

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associated with inﬂuenza-like symptoms, including fever, bone aches, headaches and dyspnea, which

usually fade away by 3 months.17 However, such

symp-toms may be confused with COVID-19 sympsymp-toms, and thus strict risk mitigation including prolonged dose titra-tion and the use of paracetamol is recommended. The

use of non-steroidal anti-inﬂammatory drugs (NSAIDs)

is currently controversial as there have been some reports stating that NSAIDs may exacerbate symptoms

in COVID-19 patients.18

Recommendations

INF-βcan be initiated or maintained safely. Dose titration and the use of paracetamol in starters is recommended. Those who

redevelop inﬂuenza-like symptoms should be checked for

COVID-19 and stop INF-βuntil a clear diagnosis is

estab-lished. Those who are still experiencing injection-related symptoms should report if the symptoms are exaggerated or different from usual.

Glatiramer Acetate

Glatiramer acetate (GA) is an MS immunomodulating drug which is not associated with an increased systemic risk of infection.19,20Furthermore, GA tends to be beneﬁcial in the Theiler’s murine encephalomyelitis virus model by inducing anti-inﬂammatory immune responses. It neither increases viral loads nor decreases anti-viral immunity.

Table 1Stratiﬁcation of COVID-19 Risk in Multiple Sclerosis Patients

Risk Factor Low Risk (Social Distancing)

Intermediate Risk (Social Stringency)

High Risk (Shielding)

Age93–95 _{<40 years} ₄₀_–_{49 years} _≥_{50 years}

Comorbidities96 (eg, diabetes mellitus, hypertension, cardiovascular disease)

Absent One Two or more

Smoking97 Non-smokers – Smokers

Type of MS10,98 _{RRMS on one of the}

low-risk medications

RRMS on one of the intermediate-risk medications

SPMS/PPMS (EDSS >4)

Ambulation index score11,98,99

0–3 (walks independently)

4–5 (unilateral support or bilateral support, walks 25 feet in≤20 seconds)

6–9 (bilateral support, walks 25 feet in >20 seconds or unable to walk 25 feet, uses wheelchair on occasions/most of the time or restricted to it)

Bulbar or respiratory symptoms related to MS99,100

No bulbar symptoms Bulbar symptoms Bulbar and respiratory symptoms

Pregnancy101 – Yes –

Obesity102_{(body mass index)} _{Normal or overweight}

(18.5−29.9 kg/m2₎

Obese (30–39.9 kg/m2₎ _{Morbidly obese (}_≥_{40 kg/m}2₎

Disease-modifying therapies99 Interferons, glatiramer acetate, natalizumab, dimethyl fumarate, teriﬂunomide

Alemtuzumab or cladribine in the past 6 months,ﬁngolimod, ocrelizumab or rituximab in the past 12 months

Alemtuzumab or cladribine in the past 12 weeks, AHSCT in the past 12 months, any other immunosuppressant

Lymphopenia2,29,93 Grade 0–1 Grade 2 Grade 3–4

Visited or living in a high-risk area for COVID-19103

No Yes (≥14 days) Yes (˂14 days)

Working in a health-care facility104

No – Yes

Abbreviations:AHSCT, autologous hematopoietic stem cell transplantation; COVID-19, coronavirus disease 2019; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; PPMS, primary progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

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Recommendations

GA can be initiated or maintained safely during the COVID-19 pandemic.

Teri

ﬂ

unomide

Teriflunomide selectively and reversibly targets activated T and B lymphocytes inducing a cytostatic effect, thus limiting their contribution to the inflammatory processes of MS pathogenesis without either compromising the adaptive immunity or increasing the incidence of serious infections in long-term follow-up.21–23 Accordingly, teriflunomide is not considered an immunosuppres-sant; however, it may lead to a mild lymphopenia23(grade 1 and 2), which usually occurs early in the treatment course and persists for an extended period. Therefore, suspension of terifl u-nomide treatment with an accelerated elimination procedure should be considered if a patient develops a serious infection.24 Mild leukopenia/neutropenia has also been reported.25

It is worth mentioning that teriflunomide and its parent com-pound, leflunomide, have demonstrated both in vitro and in vivo activity against several viruses, including the BK virus, cytome-galovirus, Epstein–Barr virus, herpes simplex virus, Theiler’s virus and John Cunningham virus (JCV).26,27Teriflunomide is slowly eliminated from plasma; it takes 8 months to 2 years to reach a plasma concentration less than 0.02 mg/L. Accelerated elimination of teriflunomide should be considered after disconti-nuation in cases where a serious infection develops. For acceler-ated elimination, the use of cholestyramine 8 g administered three times daily or 50 g of activated powdered charcoal every 12 hours for 11 days is recommended.24

Recommendations

Teriﬂunomide can be started and maintained during the

COVID-19 pandemic in the absence of concurrent infec-tion. Routine laboratory tests should be performed accord-ing to the product information. Accelerated elimination

Table 2Summary of Disease-Modifying Therapies Approved for Use in Multiple Sclerosis16,51,105

Route of Administration

Dose Principal Proposed Mechanism of Action

Interferonẞ-1a

Interferonẞ-1b IM SC SC

30 µg once per week 22–44 µg 3 times per week 0.25 mg every other day

Down-regulation of MHC expression on APCs, decrease pro-inﬂammatory cytokines, inhibit T-cell proliferation, inhibition of leukocyte migration across the BBB

Glatiramer acetate SC 20 mg once daily or 40 mg 3 times per week

Shifts pro-inﬂammatory T-helper-1 lymphocyte to regulatory T-helper2 lymphocyte

Teriﬂunomide PO 7–14 mg once daily Selective reversible inhibition of dihydroorotate

dehydrogenase, T-cell activation and cytokine production

inhibitor

Dimethyl fumarate PO 120 mg bid for 1 week then 240 mg bid

daily

Decreases pro-inﬂammatory cytokines and

decreases entry of lymphocytes into the CNS (inhibits expression of adhesion molecules)

Fingolimod PO 0.5 mg once daily Lymphocyte sequestration in secondary lymphoid tissues

Natalizumab IV 300 mg every 4 weeks Interaction withα-integrins preventing lymphocytes from

crossing BBB

Cladribine PO 3.5 mg/kg body weight divided into 2

yearly treatment courses (1–2 tablets/day

over 4–5 consecutive days)

Cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in long-lasting

depletion of lymphocytes

Ocrelizumab (anti-CD20)

IV Initially 300 mg once repeated after 2

weeks, then 600 mg every 6 months

Anti-CD20 and depletion of B lymphocytes

Mitoxantrone IV 12 mg/m2q3m (maximum cumulative dose

140 mg/m2)

Inhibits B cells and T cell and macrophage proliferation

Alemtuzumab IV 12 mg daily for 5 days, then 1 year later

12 mg daily for 3 days

Anti-CD25 and depletion of lymphocytes

Abbreviations:APC, antigen-presenting cell; BBB, blood–brain barrier; bid, twice a day; CNS, central nervous system; DNA, deoxyribonucleic acid; IM, intramuscular; IV, intravenous; µg, microgram; mg, milligram; MHC, major histocompatibility complex; PO, per oral; SC, subcutaneous.

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should be considered if the patient has COVID-19 and teriﬂunomide is to be discontinued.

Dimethyl Fumarate (DMF)

The mechanisms of action of DMF include induction of apoptosis of activated T cells, shift of CD4+T cells toward a Th2 proﬁle, and reduction of dendritic cell (DC) matura-tion. DMF has been shown to selectively reduce memory T cells in MS and decrease the overall B-cell population, in particular mature B cells.28Accordingly, it can potentially induce lymphopenia, which is reported as a worrisome sign

in the COVID-19 pandemic.29 The frequency of grade 1

lymphopenia was reported to occur in approximately 16.5% of DMF-treated patients and grade 3 (200 to <500 cells/μL) in 2.4–7%.30–32Lymphopenia is mainly encountered during the early treatment course, yet it can be severe and may

persist even after DMF withdrawal.32 PwMS with

a lymphocyte count above 800 cells/mm3 can deal with

viral infections reasonably well, provided they are relatively young and have no other comorbidities. Notwithstanding, there is no current evidence of an increased risk of

COVID-19 infection with DMF.33

Recommendations

DMF can be initiated and maintained during the COVID-19 pandemic provided there is no signiﬁcant lymphopenia (grade

≥3). The usual monitoring guidelines for DMF include

com-plete blood count (CBC) with differential leukocytic and lymphocytic counts before treatment initiation and every 3 months during theﬁrst year of treatment, followed by every 6 months thereafter, or as clinically indicated, and it should be discontinued in cases of persistent grade 3 lymphopenia for 6

or more months.34 In MS patients with conﬁrmed active

COVID-19, interruption of DMF should be considered.33,35

Fingolimod

Fingolimod has been associated with increased risk of

infec-tions compared with placebo or IFN-βand GA in

rando-mized clinical trials and post-marketing surveillance.36–40 Given its effects on lymphocyte trafficking,fingolimod could theoretically increase the risk of infections; yet, defi -nite correlation between reduction of circulating lymphocyte count and the frequency of serious or opportunistic infec-tions was critiqued by some reports, which emphasized that

infection was not signiﬁcantly increased even in patients

whose lymphocyte counts had decreased to <200 cells/ mm3.41 If the total leukocyte count is <4000 and >2500

cells/mm3 and/or the lymphocyte count is <600 and >200 cells/mm3, the dose can be reduced to every other day.42

According to some pathologicalﬁndings of pulmonary

edema and hyaline membrane formation in COVID-19, the use of immune modulators, together with ventilator sup-port, should be considered for patients with severe symp-toms to prevent the development of acute respiratory distress syndrome (ARDS). Currently, there is an ongoing

trial that aims to determine the efﬁcacy ofﬁngolimod in

the management of COVID-19.43

Recommendations

Delaying initiation ofﬁngolimod may be considered

dur-ing the coronavirus pandemic.32 For those who are on

stable treatment with regular follow-ups, it is recom-mended to advise patients to closely monitor themselves for any symptoms or signs of infection. In case of any

infection, CBC should be performed to exclude signiﬁcant

leukopenia or lymphopenia. If grade 3–4 lymphopenia

occurs at any time during the current speciﬁc

circum-stances, other treatment options should be considered.

Sudden ﬁngolimod cessation is not recommended owing

to the rebound effect that occurs approximately 2–4

months after treatment discontinuation, unless the patient

is conﬁrmed to have COVID-19.44,45In MS patients with

conﬁrmed active COVID-19, interruption of ﬁngolimod

may be considered.

Natalizumab (NTZ)

NTZ selectively compromises immune surveillance only in the central nervous system by playing a major role in active lymphocyte trafﬁcking across the blood–brain bar-rier, through binding to theα4-subunit of α4β1- andα4β7

-integrins expressed on the surface of human leukocytes

and vascular cell adhesion molecule-1.46 It is one of the

treatment options for patients with aggressive MS or sub-optimal response toﬁrst line therapies.47

Despite the increased risk for progressive multifocal leukoencephalopathy, an opportunistic life-threatening brain infection caused by JCV, the risk of acquiring sys-temic infections with NTZ is considered relatively low

compared to other high-efﬁcacy medications.48

NTZ discontinuation may trigger a rebound effect,

fre-quently occurring within 3–6 months of discontinuation;

therefore, careful evaluation of risk–beneﬁt should be con-sidered prior to NTZ cessation.49

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Recommendations

NTZ is currently viewed among the safest high-efﬁcacy

therapies to use during the COVID-19 pandemic and could be started and maintained in patients with no current or potential infection, especially in those with aggressive

MS.33For patients with active COVID-19 infection,

delay-ing the next infusion should be considered.

Cladribine

Cladribine causes selective and transient reductions of

CD19+ B cells and T cells, followed by reconstitution of

adaptive immune function. The hazard of viral infections is signiﬁcantly higher in the 3–6 months after cladribine intake as the lymphopenia nadir is 9 weeks with up to 12 weeks to recover.50

In the integrated analysis of cladribine safety, median absolute lymphocytic count (ALC) reached a nadir of 1.00 × 109cells/L at 2 months after the start of treatment during year 1. At the end of year 1 (48 weeks), median ALC had increased

to 1.21 × 109cells/L. During year 2, median ALC reached

a nadir of 0.81 × 109cells/L at 55 weeks (week 7 in year 2). Median ALC returned to the normal range by 84 weeks (week 36 in year 2). Median ALC returned to the normal range in 75% of patients by 144 weeks. Grade 3 lymphopenia was experienced by 25% of patients and grade 4 lymphopenia by <1% of patients treated with cladribine tablets.51

Recommendations

Delaying initiation of cladribine should be considered dur-ing the coronavirus pandemic. For those who have already

started treatment, delaying the second cycle52 for 3–6

months or until the risk of coronavirus infection has passed may be considered. For patients with active COVID-19 infection, delaying the second cycle of cladribine should be considered.33

Anti-CD20 Therapies

The ﬁrst therapeutic anti-CD20 monoclonal antibody

(mAb), rituximab (used off-label in MS), is a murine–

human chimera to which many patients develop antibodies and/or experience infusion-related reactions. Ocrelizumab is a second generation recombinant humanized mAb, which selectively binds to CD20-expressing B cells and triggers antibody-dependent cellular cytolysis and complement-mediated lysis. Lymphoid stem cells and plasma cells do not express CD20 and therefore are not directly targeted.53

B-cell counts are reduced within 2 weeks and remain depleted throughout ongoing treatment. The duration of

B-cell depletion was initially estimated to be 6–9 months

with rituximab treatment alone53,54 and it is now obvious from Swedish experience that rituximab remains effective

at controlling disease activity beyond 6 months.54

Anti-CD20 therapies leave the T-cell compartment of the immune system relatively intact and there have been no severe viral infections in the clinical trial programs. The main viral infection noted with anti-CD20 therapies is herpes zoster or shingles, and even then, these case tend to be mild or moderate.55

Recommendations

Delaying initiation of ocrelizumab and rituximab may be considered during the COVID-19 pandemic. In patients who are stable on treatment, one should consider delaying the next infusion.

Other Immunosuppressant Drugs

Some other immunosuppressant drugs are used off-label for managing pwMS, especially in low-income countries. A large

MS Egyptian cohort, in 2017,56showed that about 23.6% of

pwMS were receiving those drugs, including cyclophospha-mide (CPM), methotrexate (MTX), azathioprine (AZA) and mitoxantrone, as induction/maintenance therapies.56–59

Both CPM and MTX are cytotoxic drugs causing damage to immune cell DNA, thus possessing a potent immunosuppressant effect. AZA acts through inhibition of

DNA, RNA and protein synthesis.60–62 The main safety

concerns of those drugs are lymphopenia, potential risk of infections and hepatotoxicity.63,64

Mitoxantrone interacts with the enzyme topoisome-rase-2 and causes single- and double-strand breaks by

intercalating the DNA through hydrogen bonding.64,65As

has been well established for decades, mitoxantrone is a potent immunosuppressive agent targeting proliferating immune cells. It inhibits proliferation of macrophages,

B lymphocytes and T lymphocytes.66

AZA has a delayed onset of action, with the nadir lymphocyte count being reached at 135 days. Overall, lymphopenia tends to spontaneously resolve with no change in AZA dosing. Lymphopenia is a direct effect of AZA treatment, but lymphopenia-related complications have not been commonly reported. The usual monitoring strategies include weekly monitoring of CBC and liver

enzymes for the ﬁrst 4 weeks of therapy, or until the

maintenance dose is achieved, and then every 3 months.67

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Recommendations

Clinicians should consider delaying initiation of CPM, MTX and mitoxantrone during the COVID-19 pandemic. Interruption of CPM, MTX and mitoxantrone may be considered. AZA can be started with weekly monitoring

of CBC and transaminases for theﬁrst 4 weeks of therapy.

Alemtuzumab (AMZ)

AMZ is a humanized anti-CD52 mAb.68,69It induces lysis

and apoptosis of cells highly expressing CD52, namely

T and B lymphocytes,70 via antibody-dependent cellular

cytotoxicity (ADCC) and complement-dependent cytotoxi-city, leading to a marked global lymphocyte depletion.71,72 AMZ-treated patients exhibit a nearly complete depletion

of circulating CD4+ lymphocytes within a few hours of

administration, with a nadir between days 3 and 7.73,74The repopulation of T lymphocytes starts by month 3 and the return to the lower limit of the normal values occurs by

month 6–12; however, this could be delayed for up to 24

months. B cells start to repopulate from 6 weeks onward, return to baseline by 3 months and exceed baseline levels from 6 months.75–78

Overall, in key clinical trials, infections were more common in AMZ-treated patients compared to those trea-ted with INFβ-1a.73,74,79,80 The accumulations of herpes infections during the CARE-MS studies led to the

imple-mentation of prophylactic acyclovir treatment (0–4 weeks

after AMZ infusion).81 The treating physician should be

vigilant to possible opportunistic infections, particularly in

the ﬁrst few months after AMZ infusion.82

AMZ administration is associated with acute induction

of some pro-inﬂammatory cytokines, such as tumor

necro-sis factor-alpha (TNF-α), interleukin-6 (IL-6) and

inter-feron-gamma (INF-γ), which peaks 2–6 hours after

infusions and causes the“cytokine-release syndrome”.83 Thus, in the COVID-19 pandemic AMZ carries a signiﬁcant risk of catching the infection, besides the theo-retical potential of aggravating the inﬂammatory phase of the disease caused by the cytokine storm.

Recommendations

Clinicians should consider delaying initiation of AMZ dur-ing the COVID-19 pandemic. In patients with highly active

relapsing–remitting multiple sclerosis (RRMS), the use of

an alternative treatment is to be considered, eg, NTZ (or DMF if serum anti-JCV antibodies are positive). If theﬁrst or second cycle has already been administered, the patient

should adhere to strict social stringency or shielding, or even self-isolation for 3 months or until a CBC demon-strates lymphocytic recovery. If another treatment cycle is due, it could be postponed.

Recommendations for the initiation and maintenance of

DMTs in MS patients are summarized inFigure 1.

Management of Relapse

Patients who present with new or worsening of neurologi-cal symptoms and have symptoms suggestive of COVID-19 (fever, dry cough, sore throat, headache or bone pains, loss of smell and/or taste) are to be sent for nasopharyn-geal and oropharynnasopharyn-geal swab or wash and PCR testing. If

the diagnosis of COVID-19 is conﬁrmed, health

authori-ties should be notiﬁed according to national requirements. If tests are repeatedly negative, other causes of fever should be searched for and treated accordingly.

If there are no symptoms or signs of any infection, a diagnosis of a true relapse can be made, and standard treat-ment should be applied. Caution is warranted that pseudo-relapse might be followed by a bonaﬁde MS relapse.84

A telephone questionnaire can be used to assess the Expanded Disability Status Scale (EDSS) score in cases where patients are unable to attend at their health facility

owing to quarantine or curfew.85

Relapses that do not or only minimally affect activities of daily living and affect only sensory functional domains are considered mild and do not require steroid treatment under the current pandemic circumstances. Any other

relapse, considered moderate or severe,86 should receive

appropriate treatment.

It is advisable to limit the use of steroids during the COVID-19 pandemic. Pulsed high-dose/continuous oral steroids are immunosuppressive and may, at least theore-tically, increase the risk of a COVID-19 viral infection or severity of related symptoms. If steroids are to be given anyway, patients are encouraged to receive standard

high-dose corticosteroids intravenously at home87 with strict

self-isolation. Following high-dose corticosteroids, oral tapering is not necessary unless considerable residual symptoms are still encountered. Early clinical trials used steroid tapering after high-dose intravenous corticosteroids to combat potential acute adrenal insufﬁciency or to main-tain the therapeutic effect; however, subsequent studies have shown that this tapering is not necessary after a brief steroid course that does not signiﬁcantly suppress the hypothalamic–pituitary–adrenal axis,88nor does taper-ing contribute to recovery.89

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Intravenous immunoglobulin (IVIG) exhibits

anti-inﬂammatory effects via inhibition of

complement-mediated tissue damage and modulation of the cytokine

network. It suppresses the production of pro-inﬂammatory

cytokines while increasing the production of

anti-inﬂammatory mediators.90Also, it has ian

mmunomodula-tory inﬂuence on different cells of the innate and adaptive

immune compartments.91

Figure 1Algorithm of initiation and maintenance of DMTs in RRMS patients during COVID-19 pandemic.106

Abbreviations:COVID-19, coronavirus disease 2019; DMF, dimethyl fumarate; DMT, disease-modifying therapy; INF, interferon; JCV, John Cunningham virus; RRMS, relapsing–remitting multiple sclerosis.

Figure 2Algorithm of relapse management in RRMS patients during COVID-19 pandemic.

Abbreviations:COVID-19, coronavirus disease 2019; IVIG, intravenous immunoglobulins; IVMP, intravenous methylprednisolone; RRMS, relapsing–remitting multiple sclerosis.

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IVIG therapy has a minimal impact on immune

function.92 Therefore, IVIG can currently be considered

as a good alternative if steroids are contraindicated, poorly tolerated or ineffective, or if hospitalization is impossible. Plasma exchange may not be a suitable option in the treatment algorithm because of its invasive nature and the need for prolonged hospital stay.

Recommendations for the management of relapse

dur-ing COVID-19 are summarized inFigure 2.

Summary of Recommendations

● Before initiating a DMT that may lower immunity,

PwMS should remain in quarantine for at least 14 days to exclude potential COVID-19 infection.

● pwMS would not normally need to stop taking their

DMT as a result of the threat of the virus.

● Patients on a “treatment-escalation/modiﬁcation”

pathway are not under immediate pressure to change, unless there are other factors (disease activity, JCV positivity, etc).

● Patients on immune reconstitution DMTs can rely on

their long-term effect with delaying re-dosing. ● It seems wiser to select a treatment that does not reduce

speciﬁc immune cells (lymphocytes) (eg, interferons, glatiramer acetate or natalizumab). Medications that reduce lymphocytes over longer intervals (eg, alemtu-zumab, cladribine, ocrelizumab and rituximab) or those which may reduce the ability of the immune system to

respond to infection (eg,ﬁngolimod, dimethyl

fuma-rate, teriﬂunomide and siponimod) should carefully be considered with regard to the risks and beneﬁts during the COVID-19 pandemic.

● pwMS who are currently on alemtuzumab, cladribine,

ocrelizumab, rituximab, ﬁngolimod, dimethyl

fuma-rate, teriﬂunomide or siponimod and are living in

a community with a COVID-19 outbreak should isolate as much as possible to reduce their risk of infection.

● For patients with active COVID-19 infection, it is

mandatory to stop all DMTs. The timing of resuming

treatment is not well deﬁned but may depend on

serial COVID-19-negative PCR tests within 3–4

weeks of resolution of symptoms.

Although these recommendations can offer guidance toward optimized practice, management of patients with multiple sclerosis during the COVID-19 pandemic is still very challenging given the uncertainty of the current situa-tion and the lack of evidence.

Disclosure

Thomas Berger has participated in the last 2 years in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical

com-panies marketing treatments for multiple sclerosis:

Almirall, Biogen, Bionorica, Celgene, MedDay, Merck,

Novartis, Roche, Sanoﬁ Aventis/Genzyme, TG

Therapeutics and TEVA.His institution has receivedﬁ

nan-cial support in the last 2 years by unrestricted research

grants (Biogen, Novartis, SanoﬁAventis/Genzyme, Roche,

TEVA) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Biogen, Merck, Novartis,

Roche, Sanoﬁ Aventis/Genzyme, TEVA. The authors

report no other conﬂicts of interest in this work.

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